The present invention relates to novel prodrug forms of 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, to pharmaceutical compositions containing the prodrug forms, and to methods of using the prodrug forms.
European Patent Application Publication No. 590789A1 and U.S. Pat. No. 5,446,051 disclose that certain decahydroisoquinoline derivatives are AMPA receptor antagonists, and as such are useful in the treatment of many different conditions, including pain. In addition, WO 98/45270, published Oct. 15, 1998, discloses that certain selective GluR5 antagonists are useful for treating pain.
It is an object of the present invention to provide diesters of 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid which provide substantially improved bioavailability of the parent diacid in a patient. In addition, it is an object of the present invention to provide diesters of 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid which are substantially converted to the parent diacid in the patient.
It has now been found that novel diesters of the diacid, 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, possess substantially improved bioavailability as compared to the diacid. In addition, the diesters are substantially converted to the diacid in the patient. The diacid is generically disclosed in U.S. Pat. No. 5,446,051, issued Aug. 29, 1995, and specifically disclosed in, WO 98/45270, published Oct. 15, 1998, as a selective GluR5 antagonist for treatment of pain.
Thus, the present invention provides compounds of formula I: 
wherein R1 and R2 are each independently C1-C20 alkyl, C2-C6 alkenyl, C1-C6 alkylaryl, C1-C6 alkyl(C3-C10) cycloalkyl, C1-C6 alkyl-N, Nxe2x80x94C1-C6 dialkylamine, C1-C6 alkyl-pyrrolidine, C1-C6 alkyl-piperidine, or C1-C6 alkyl-morpholine; or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of antagonizing the GluR5 receptor, which comprises administering to a patient an effective amount of a compound of formula I.
In addition, the present invention provides a method for the treatment of pain, which comprises administering to a patient an effective amount of a compound of formula I.
The present invention further provides a method for the treatment of migraine, which comprises administering to a patient an effective amount of a compound of formula I.
The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of pain.
The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of migraine.
As used herein, the term xe2x80x9cprodrugxe2x80x9d refers to a diester derivative of a dicarboxylic acid functional drug, which derivative, when administered to a patient is converted into the diacid (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the parent dicarboxylic acid (drug ) is released.
As used herein the term xe2x80x9cCompound Axe2x80x9d refers to 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
As used herein the term xe2x80x9cCompound Bxe2x80x9d refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diethyl ester.
As used herein the term xe2x80x9cCompound Cxe2x80x9d refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, dimethyl ester.
As used herein the term xe2x80x9cCompound Dxe2x80x9d refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diisopropyl ester.
As used herein the term xe2x80x9cCompound Exe2x80x9d refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diisobutyl ester.
As used herein the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term xe2x80x9cC1-C10 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term xe2x80x9cC1-C20 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like.
As used herein, the terms xe2x80x9cMexe2x80x9d, xe2x80x9cEtxe2x80x9d, xe2x80x9cPrxe2x80x9d, xe2x80x9ciPrxe2x80x9d, xe2x80x9cBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein the term xe2x80x9cC2-C6 alkenylxe2x80x9d refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C2-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
As used herein, the term xe2x80x9carylxe2x80x9d refers to monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
As used herein, the term xe2x80x9cC1-C6 alkylarylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkylarylxe2x80x9d are the following: 
and the like.
As used herein the term xe2x80x9c(C3-C10)cycloalkylxe2x80x9d refers to a saturated hydrocarbon ring structure containing from three to ten carbon atoms. Typical C3-C10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It is understood that xe2x80x9c(C3-C8)cycloalkylxe2x80x9d and xe2x80x9c(C4-C6)cycloalkylxe2x80x9d is included within the term xe2x80x9c(C3-C10)cycloalkylxe2x80x9d.
As used herein, the term xe2x80x9cC1-C6 alkyl(C3-C10)cycloalkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C3-C10)cycloalkyl attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkyl(C3-C10)cycloalkylxe2x80x9d are the following: 
and the like
As used herein the term xe2x80x9cN,Nxe2x80x94C1-C6 dialkylaminexe2x80x9d refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term xe2x80x9cN,Nxe2x80x94C1-C6 dialkylaminexe2x80x9d are xe2x80x94N(CH3)2, xe2x80x94N(CH2CH3)2, xe2x80x94N(CH2CH2CH3)2, xe2x80x94N(CH2CH2CH2CH3)2, and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-N,Nxe2x80x94C1-C6 dialkylaminexe2x80x9d refers to straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N,Nxe2x80x94C1-C6 dialkylamine attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkyl-N,Nxe2x80x94C1-C6 dialkylaminexe2x80x9d are the following: 
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-pyrrolidinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-pyrrolidinexe2x80x9d are the following: 
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-piperidinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-piperidinexe2x80x9d are the following: 
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-morpholinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a morpholine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-morpholinexe2x80x9d are the following: 
and the like.
The designation 
refers to a bond that protrudes forward out of the plane of the page.
The designation 
refers to a bond that protrudes backward out of the plane of the page.
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex1-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981.
The compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, xe2x80x9cStereochemistry of Organic Compoundsxe2x80x9d, John Wiley and Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
The compounds of formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art. For example, various starting materials and general procedures which may be employed by one of ordinary skill in the art in the preparation of compounds of formula I are described in U.S. Pat. No. 5,446,051, issued Aug. 29, 1995, which is hereby incorporated by reference, and WO 98/45270, published Oct. 15, 1998.
More specifically, compounds of formula I can be prepared by following the procedures as set forth in Scheme I. This scheme is not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. 
In Scheme I, compound A is esterified to provide the diester of formula I under standard conditions well known in the art. For example, compound A is dissolved in a suitable organic solvent and treated with a suitable acid, such as hydrochloric acid. Examples of suitable organic solvents include, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl alcohol, 2-ethylbutyl alcohol, n-heptyl alcohol, n-octyl alcohol, and the like. The reaction is heated at about 40xc2x0 C. to about 60xc2x0 C. for about 4 hours to about 16 hours. The product is then isolated and purified using techniques well known to one of ordinary skill in the art, such as extraction techniques and chromatography.
For example, the above reaction is cooled, diluted with a suitable organic solvent, such as ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I. This material may be further purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane.
Alternatively, compound A is dissolved in a suitable organic solvent and treated with an excess of thionyl chloride. Examples of suitable organic solvents are anhydrous methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl alcohol, 2-ethylbutyl alcohol, n-heptyl alcohol, n-octyl alcohol, and the like. The solution is stirred at reflux for about 1 to 3 hours, and at room temperature for about 8 to 16 hr. The mixture is then concentrated under vacuum, and the residue is purified in a manner analogous to the procedures described above to provide the prodrug diester of formula I.
The pharmaceutically acceptable salts of formula I are readily prepared by one of ordinary skill in the art using standard techniques and procedures. For example, the above product is suspended in diethyl ether, which has been saturated with HCl gas. The mixture is stirred for about 1 to 3 hours. The precipitate is then filtered and washed with diethyl ether under vacuum to provide the pharmaceutically acceptable salt of the prodrug diester of formula I.
The following examples illustrate the invention and represent typical syntheses of the compounds of formula I as described generally above. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: xe2x80x9ceqxe2x80x9d or xe2x80x9cequiv.xe2x80x9d refers to equivalents; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9cminxe2x80x9d refers to minutes; xe2x80x9chxe2x80x9d refers to hours; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cxcex4xe2x80x9d refers to part per million down-field from tetramethylsilane; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide; xe2x80x9cDMSOxe2x80x9d refers to methyl sulfoxide; xe2x80x9caqxe2x80x9d refers to aqueous; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9ciPrOAcxe2x80x9d refers to isopropyl acetate; xe2x80x9cMeOHxe2x80x9d refers to methanol; xe2x80x9cMTBExe2x80x9d refers to tert-butyl methyl ether, and xe2x80x9cRTxe2x80x9d refers to room temperature.